chr17-76007414-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001988.4(EVPL):​c.5791G>A​(p.Val1931Met) variant causes a missense change. The variant allele was found at a frequency of 0.000112 in 1,603,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000072 ( 0 hom. )

Consequence

EVPL
NM_001988.4 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.16
Variant links:
Genes affected
EVPL (HGNC:3503): (envoplakin) This gene encodes a member of the plakin family of proteins that forms a component of desmosomes and the epidermal cornified envelope. This gene is located in the tylosis oesophageal cancer locus on chromosome 17q25, and its deletion is associated with both familial and sporadic forms of oesophageal squamous cell carcinoma. Patients suffering from the autoimmune mucocutaneous disorder, paraneoplastic pemphigus, develop antibodies against the encoded protein. [provided by RefSeq, Jul 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.04193011).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EVPLNM_001988.4 linkc.5791G>A p.Val1931Met missense_variant 22/22 ENST00000301607.8 NP_001979.2 Q92817
EVPLNM_001320747.2 linkc.5857G>A p.Val1953Met missense_variant 22/22 NP_001307676.1 Q92817K7EKI0B7ZLH8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EVPLENST00000301607.8 linkc.5791G>A p.Val1931Met missense_variant 22/221 NM_001988.4 ENSP00000301607.3 Q92817
EVPLENST00000586740.1 linkc.5857G>A p.Val1953Met missense_variant 22/221 ENSP00000465630.1 K7EKI0
EVPLENST00000589231.1 linkc.28G>A p.Val10Met missense_variant 1/23 ENSP00000467717.1 K7EQ87
EVPLENST00000587569.5 linkn.6260G>A non_coding_transcript_exon_variant 20/202

Frequencies

GnomAD3 genomes
AF:
0.000493
AC:
75
AN:
152180
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00159
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000141
AC:
35
AN:
247836
Hom.:
0
AF XY:
0.000127
AC XY:
17
AN XY:
133936
show subpopulations
Gnomad AFR exome
AF:
0.00173
Gnomad AMR exome
AF:
0.0000291
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000659
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000266
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.0000723
AC:
105
AN:
1451642
Hom.:
0
Cov.:
31
AF XY:
0.0000749
AC XY:
54
AN XY:
720540
show subpopulations
Gnomad4 AFR exome
AF:
0.00165
Gnomad4 AMR exome
AF:
0.0000674
Gnomad4 ASJ exome
AF:
0.0000385
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.0000349
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000335
Gnomad4 OTH exome
AF:
0.0000834
GnomAD4 genome
AF:
0.000492
AC:
75
AN:
152298
Hom.:
0
Cov.:
32
AF XY:
0.000577
AC XY:
43
AN XY:
74466
show subpopulations
Gnomad4 AFR
AF:
0.00159
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000279
Hom.:
0
Bravo
AF:
0.000502
ESP6500AA
AF:
0.00113
AC:
5
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000148
AC:
18
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 30, 2021The c.5791G>A (p.V1931M) alteration is located in exon 22 (coding exon 22) of the EVPL gene. This alteration results from a G to A substitution at nucleotide position 5791, causing the valine (V) at amino acid position 1931 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.43
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.099
T;T;.
Eigen
Benign
-0.031
Eigen_PC
Benign
-0.027
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.73
T;T;T
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.042
T;T;T
MetaSVM
Benign
-0.54
T
MutationAssessor
Benign
0.69
.;N;.
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-1.1
.;N;.
REVEL
Benign
0.15
Sift
Uncertain
0.013
.;D;.
Sift4G
Uncertain
0.047
D;D;D
Polyphen
0.52
.;P;.
Vest4
0.15, 0.20
MVP
0.67
MPC
0.25
ClinPred
0.040
T
GERP RS
3.5
Varity_R
0.24
gMVP
0.62

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs146869766; hg19: chr17-74003495; API